Transformation of melanocyte to malignant melanoma is a multistage process which includes changes both at the genomic and gene expression level. The studies proposed here aim at the elucidation of a newly identified inhibitor protein which is active in malignant melanoma derived cells and thus have the potential to represent an important change in the development of this tumor type. We have previously identified and characterized a UV-response element (TGACAACA) and its bound proteins in rat fibroblast and human keratinocyte cells. In characterizing the URE in cells of malignant melanoma patients a striking difference was noted in the expression pattern and activities of URE-bound proteins (URP) when compared with those observed in their non- transformed counterpart. While nuclear proteins of non-transformed cells exhibit low level of binding activity to the URE with a notable increase in this binding following UV-irradiation, non,treated melanoma cells, in contrast, exhibit substantially stronger binding which is abolished following their exposure to UV-irradiation. The striking decrease in URP activities is attributed to the activation of an inhibitor protein (I-URP) by UV-irradiation of malignant melanoma cells. The proposed studies are aimed at the characterization of I-URP via (1) identification of the putative inhibitor; (2) characterization of I-URP activities; (3) functional assessment of I-URP activities in melanoma and melanocyte cell lines; (4) identification of signal transduction pathway(s) that mediate I-URP activities, and (5) elucidating on the regulation of I-URP expression through characterizing its 5' non-coding region. Overall, successful completion of the proposed studies will provide substantial new understanding of mechanisms involved in the conversion of normal melanocytes to malignant melanomas, and possibly in the development of other radiation related neoplasms.